Tobacco addiction is the leading preventable cause of cancer and cardiovascular diseases. Although the last two decades have witnessed accelerated efforts to develop effective smoking cessation strategies, the long-term success rates have been disappointing. The majority of smokers relapse within two weeks of a cessation attempt. Stress is one of the most commonly reported precipitants of smoking relapse. Mechanisms responsible for the stress-precipitated relapse are not known. Without specific knowledge of the stress-related psychobiological changes in smokers, targeted efforts to reduce smoking relapse will remain limited. The long-term goal of our research is to determine the psychobiological mechanisms responsible for smoking relapse. The specific goal of this project is to determine the extent to which changes in the pituitaryadrenocortical activity during early abstinence and in response to acute stress predict relapse in smokers attempting to quit. Our central hypothesis is that exaggerated adrenocorticotropic hormone (ACTH) and cortisol changes during early abstinence, as measured during ambulatory monitoring and in response to stress, predict time to relapse. This hypothesis is based on our previous studies and on the observation that psychosocial stressors increase the risk for smoking relapse. The proposed study will include ambulatory measurement of diurnal cortisol levels and awakening rise in cortisol during 24 hours while participants are still smoking at their normal rates (baseline), and during the period of 24-48 hours of abstinence. The study will also include measurement of plasma ACTH, cortisol, blood pressure, and withdrawal symptoms during two laboratory stress sessions (during ad libitum smoking and after 48 hours of abstinence). During each session participants will perform three stressful challenges (public speaking, math, and cold pressor). This research focuses on the hypothalamic-pituitary-adrenocortical axis, an important biological system recently implicated in addiction. The research integrates hormonal, hemodynamic, and psychological indices to determine stress response patterning among smokers during this critical period of a quit attempt, and uses this information in a prospective fashion to identify specific biobehavioral markers of relapse over a 12-month period. An important goal for this research is to determine differences in psychobiological changes between men and women, and establish the extent to which these differences predict relapse. The results will be important in the development of optimal diagnostic and intervention strategies for smokers interested in cessation and at high risk for relapse. Reducing relapse rates will contribute significantly towards decreasing tobacco use and its devastating effects.